Phase I study of concurrent real-time tumor-tracking thoracic radiation therapy with paclitaxel and carboplatin in locally advanced non-small cell lung cancer

Introduction: Although paclitaxel with carboplatin and thoracic radiotherapy has improved survival for patients with locally advanced unresectable non-small cell lung cancer (NSCLC), the optimal dose of paclitaxel has not been well defined in Japan. This study was conducted to determine the maximum tolerated dose (MTD) and recommended dose (RD) of paclitaxel in combination with carboplatin and concurrent real-time tumor-tracking thoracic radiation therapy (thoracic RTRT). Patients and methods: Previously untreated patients with histologically confirmed, locally advanced unresectable NSCLC were eligible. Before treatment, gold markers were inserted into the lung and the mediastinum of all patients. RTRT comprised a total of 66 Gy at 2 Gy/fraction, 5 days/week, for 7 weeks. Patients received paclitaxel at a starting dose of 40 mg/m2 followed by carboplatin at a fixed area under the curve (AUC) of 2, as a weekly regimen with RTRT. The dose of paclitaxel was escalated by 5 mg/m2 per level. Results: Eight patients with locally advanced unresectable NSCLC were enrolled and treated with two dose levels of paclitaxel (40 mg/m2 and 45 mg/m2), carboplatin (AUC = 2) and RTRT. No dose limiting toxicities (DLTs) were observed at Level 1 (paclitaxel, 40 mg/m2 and carboplatin, AUC = 2). At Level 2 (paclitaxel, 45 mg/m2 and carboplatin, AUC = 2), two of five patients experienced DLTs, in the form of esophagitis and discontinuation of chemotherapy more than twice. The MTD and RD of paclitaxel were thus defined as 45 mg/m2 and 40 mg/m2, respectively. Conclusions: This phase I study was well tolerated and the RD of paclitaxel and carboplatin with RTRT is 40 mg/m2 at AUC = 2, respectively. Further studies are warranted to evaluate the efficacy of this regimen

Microarray Analysis of Perinatal-Estrogen-Induced Changes in Gene Expression Related to Brain Sexual Differentiation in Mice

<div><p>Sexual dimorphism of the behaviors or physiological functions in mammals is mainly due to the sex difference of the brain. A number of studies have suggested that the brain is masculinized or defeminized by estradiol converted from testicular androgens in perinatal period in rodents. However, the mechanisms of estrogen action resulting in masculinization/defeminization of the brain have not been clarified yet. The large-scale analysis with microarray in the present study is an attempt to obtain the candidate gene(s) mediating the perinatal estrogen effect causing the brain sexual differentiation. Female mice were injected with estradiol benzoate (EB) or vehicle on the day of birth, and the hypothalamus was collected at either 1, 3, 6, 12, or 24 h after the EB injection. More than one hundred genes down-regulated by the EB treatment in a biphasic manner peaked at 3 h and 12-24 h after the EB treatment, while forty to seventy genes were constantly up-regulated after it. Twelve genes, including <i>Ptgds, Hcrt</i>, <i>Tmed2</i>, <i>Klc1</i>, and <i>Nedd4</i>, whose mRNA expressions were down-regulated by the neonatal EB treatment, were chosen for further examination by semiquantitative RT-PCR in the hypothalamus of perinatal intact male and female mice. We selected the genes based on the known profiles of their potential roles in brain development. mRNA expression levels of <i>Ptgds, Hcrt</i>, <i>Tmed2</i>, and <i>Nedd4</i> were significantly lower in male mice than females at the day of birth, suggesting that the genes are down-regulated by estrogen converted from testicular androgen in perinatal male mice. Some genes, such as <i>Ptgds</i> encoding prostaglandin D2 production enzyme and <i>Hcrt</i> encording orexin, have been reported to have a role in neuroprotection. Thus, <i>Ptgds</i> and <i>Hcrt</i> could be possible candidate genes, which may mediate the effect of perinatal estrogen responsible for brain sexual differentiation. </p> </div

Changes in expressions of <i>Tmed2</i>, <i>Klc1</i>, <i>Nedd4, Hcrt</i>, <i>Meis2</i>, <i>Neurod6</i>, <i>Pitx2, Ptgds</i>, <i>Vtn</i>, Fn <i>1</i>, <i>Apod</i>, and <i>Igf2</i> genes in the female mouse hypothalamus 3 h (A), 12 h (B), or 24 h (C) after the EB treatment.

<p>Values in EB-treated (solid circle) and vehicle-treated controls (open circle) are indicated as signal intensity in microarray hybridization. Values are means±SEM. Values marked with asterisks (* or **) are significantly different from vehicle-treated controls at each time point (P < 0.05 or P < 0.01, two-way ANOVA (treatment and time as main factors) followed by the Bonferroni test). </p

Association of Time Course of Thrombectomy and Outcomes for Large Acute Ischemic Region: RESCUE–Japan LIMIT Subanalysis

Background The effectiveness of endovascular thrombectomy (EVT) has been proven even in patients with large cerebral infarction in the early time window. However, the association of the time course with the treatment effect is unknown. The aim of this analysis was to evaluate the influence of the time course from stroke onset to reperfusion on the therapeutic effect of EVT. Methods The subjects were patients with occlusion of large vessels and sizable strokes on imaging (Alberta Stroke Program Early Computed Tomographic score 3–5) in RESCUE–Japan LIMIT (Recovery by Endovascular Salvage for Cerebral Ultra‐Acute Embolism–Japan Large Ischemic Core Trial), a multicenter, randomized, clinical open‐label trial of EVT versus medical care alone. In the current analysis, the clinical and time course characteristics associated with a favorable outcome (modified Rankin scale [mRS] score of 0–2 and 0–3 at 90 days) were examined in patients treated with EVT. Results The analysis included 71 patients (median age, 77 years; median National Institutes of Health Stroke Scale score on admission, 21). Occlusion sites were the internal carotid artery (48%), proximal segment of the middle cerebral artery (72%) and tandem lesions (20%). Of these patients, 23 (32%) had an mRS score of 0 to 3 and 12 (17%) had an mRS score of 0 to 2 at 90 days. In multivariate analysis, there were independent associations of onset to reperfusion time (odds ratio [OR], 0.991 [95% CI, 0.984–0.999]; P=0.01) and puncture to reperfusion time (OR , 0.952 [95% CI, 0.917–0.988]; P<0.001) with an mRS score of 0 to 3 at 90 days, and puncture to reperfusion time (OR, 0.930 [95% CI, 0.872–0.991]; P=0.004) with an mRS score of 0 to 2 at 90 days. Conclusion Earlier reperfusion was related to a favorable outcome in patients with acute large‐vessel occlusion with a large ischemic region. Onset to reperfusion time and especially puncture to reperfusion time were independently associated with a favorable outcome. These results suggest the importance of timing and uninterrupted EVT in this patient population

Expressions of <i>Tmed2</i>, <i>Klc1</i>, <i>Nedd4, Hcrt</i>, <i>Meis2</i>, <i>Neurod6</i>, <i>Pitx2, Ptgds</i>, <i>Vtn</i>, Fn <i>1</i>, <i>Apod</i>, and <i>Igf2</i> genes in the hypothalamus of perinatal intact male and female mouse at embryonic day 16 (E16), E18, the day of birth (D0), and two days after the birth (D2).

<p>mRNA levels of these genes were determined semiquantitatively by RT-PCR followed by analysis with Image J from NIH. Gene expression levels in intact male (solid circle) and female hypothalamus (open circle) were indicated in relation to <i>Actb</i>. Values are means±SEM. Values marked with asterisks (* or **) are significantly different from female mice at each time point (P < 0.05 or P < 0.01, two-way ANOVA (sex and age as main factors) followed by the Bonferroni test). Section signs indicate significant effect between sex as a main factor of two-way ANOVA.</p

The number of Affymetrix probe ID, expressions of which were increased or decreased by neonatal estradiol bezoate (EB) treatment, in the hypothalamus of female mice.

<p>A, Numbers of genes showing a 2-fold or greater expression in EB-treated group compared with vehicle-treated control group; B, Numbers of genes showing a 0.5-fold or less expression in EB-treated group compared with vehicle-treated control group. Female mice were subcutaneously treated with EB (7.5 μg) on the day of birth and then the hypothalamus were collected at either 1, 3, 6, 12,or 24 h after the EB treatment. Difference of gene expression between EB- and vehicle-treated control mice was determined by GeneSpring GX 7.3 software. </p

Phase I study of concurrent real-time tumor-tracking thoracic radiation therapy with paclitaxel and carboplatin in locally advanced non-small cell lung cancer

Introduction: Although paclitaxel with carboplatin and thoracic radiotherapy has improved survival for patients with locally advanced unresectable non-small cell lung cancer (NSCLC), the optimal dose of paclitaxel has not been well defined in Japan. This study was conducted to determine the maximum tolerated dose (MTD) and recommended dose (RD) of paclitaxel in combination with carboplatin and concurrent real-time tumor-tracking thoracic radiation therapy (thoracic RTRT). Patients and methods: Previously untreated patients with histologically confirmed, locally advanced unresectable NSCLC were eligible. Before treatment, gold markers were inserted into the lung and the mediastinum of all patients. RTRT comprised a total of 66 Gy at 2 Gy/fraction, 5 days/week, for 7 weeks. Patients received paclitaxel at a starting dose of 40 mg/m2 followed by carboplatin at a fixed area under the curve (AUC) of 2, as a weekly regimen with RTRT. The dose of paclitaxel was escalated by 5 mg/m2 per level. Results: Eight patients with locally advanced unresectable NSCLC were enrolled and treated with two dose levels of paclitaxel (40 mg/m2 and 45 mg/m2), carboplatin (AUC = 2) and RTRT. No dose limiting toxicities (DLTs) were observed at Level 1 (paclitaxel, 40 mg/m2 and carboplatin, AUC = 2). At Level 2 (paclitaxel, 45 mg/m2 and carboplatin, AUC = 2), two of five patients experienced DLTs, in the form of esophagitis and discontinuation of chemotherapy more than twice. The MTD and RD of paclitaxel were thus defined as 45 mg/m2 and 40 mg/m2, respectively. Conclusions: This phase I study was well tolerated and the RD of paclitaxel and carboplatin with RTRT is 40 mg/m2 at AUC = 2, respectively. Further studies are warranted to evaluate the efficacy of this regimen